Targeting tumour vasculature as a molecular approach to cancer chemotherapies is becoming one of the highest scientific priorities. Two drug models are emerging, i.e. one that prevents the formation of new blood vessels in the tumour (antiangiogenesis) and one that targets vascular destruction.
Disruption of even a small proportion of the tumour vasculature has been demonstrated to induce wide ranging tumour death and retardation of metastasis, since a single blood vessel is responsible for supporting the survival of many tumour cells. Endothelial cells, which form the major component of the vasculature, are highly dependent upon the tubulin cytoskeleton for their motility, invasion, attachment, alignment and proliferation (Denekamp, J, Br J Cancer, 45, 136-139 (1982)). Agents which disrupt the endothelial microtubule network will therefore cause a rapid collapse in tumour blood flow and a prolonged period of vascular shutdown, culminating in extensive tumour-cell necrosis (Tozer et al., Nat Rev Cancer, 5, 423-435 (2005), Lippert J W, Bioorg Med Chem, 15, 605-615 (2007)).
One of the most potent classes of cancer therapeutic drugs are the vascular disrupting agents (VDAs) which characteristically have good in vitro cell cytotoxicities but often show poor specificity for killing tumour over normal tissues in vivo. Furthermore, many VDAs such as the tubulin binding agents are water insoluble and require formulation before evaluation in the clinic. The present invention aims to address the aforementioned problems.
Colchicine and its analogues are potent VDAs causing haemorrhage and subsequent extensive necrosis in tumours (Tozer et al., Nat Rev Cancer, 5, 423-435 (2005)), as a direct consequence of tubulin binding and induction of microtubule depolymerisation (Chaudri et al., J Mol Biol, 303, 679-692 (2000)). Colchicine has not, however, shown intrinsic value as a clinically applicable anticancer therapeutic due to a high level of toxicity and consequent very narrow therapeutic index (Tozer et al., Nat Rev Cancer, 5, 423-435 (2005); Quinn et al., J Med Chem, 24, 636-639 (1981)). It would be desirable, therefore, to be able to target a VDA such as colchicine selectively to a tumour.
The present inventors have developed a system for overcoming the toxic effect of systemic administration of potent anti-cancer agents in particular vascular disrupting agents.